WO2023020902A1 - Dispositif et procédé d'observation d'une sonde biologique - Google Patents

Dispositif et procédé d'observation d'une sonde biologique Download PDF

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Publication number
WO2023020902A1
WO2023020902A1 PCT/EP2022/072401 EP2022072401W WO2023020902A1 WO 2023020902 A1 WO2023020902 A1 WO 2023020902A1 EP 2022072401 W EP2022072401 W EP 2022072401W WO 2023020902 A1 WO2023020902 A1 WO 2023020902A1
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Prior art keywords
cameras
camera
biological probe
microscope
camera images
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PCT/EP2022/072401
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English (en)
Inventor
Ramona Seliger
Thomas Engel
Martin Kraus
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Siemens Healthcare Gmbh
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Publication of WO2023020902A1 publication Critical patent/WO2023020902A1/fr

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    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/0004—Microscopes specially adapted for specific applications
    • G02B21/002—Scanning microscopes
    • G02B21/0024—Confocal scanning microscopes (CSOMs) or confocal "macroscopes"; Accessories which are not restricted to use with CSOMs, e.g. sample holders
    • G02B21/0052—Optical details of the image generation
    • G02B21/0056—Optical details of the image generation based on optical coherence, e.g. phase-contrast arrangements, interference arrangements
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/0004—Microscopes specially adapted for specific applications
    • G02B21/002—Scanning microscopes
    • G02B21/0024—Confocal scanning microscopes (CSOMs) or confocal "macroscopes"; Accessories which are not restricted to use with CSOMs, e.g. sample holders
    • G02B21/0052—Optical details of the image generation
    • G02B21/0068—Optical details of the image generation arrangements using polarisation
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/0004—Microscopes specially adapted for specific applications
    • G02B21/0092—Polarisation microscopes
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/36—Microscopes arranged for photographic purposes or projection purposes or digital imaging or video purposes including associated control and data processing arrangements
    • G02B21/365—Control or image processing arrangements for digital or video microscopes

Definitions

  • the invention relates to a device and a method for observing a biological probe .
  • Quantitative phase microscopy has emerged as a tool for biomedical research, due to its capability to make optical thickness variation of a specimen visible without the need of staining .
  • quantitative phase microscopy may be used for cellular level red blood cell (RBC ) volume analysis .
  • phase microscopy based on di f fraction phase microscopy which is a common-path quantitative phase imaging ( QPI ) method .
  • QPI quantitative phase imaging
  • spatial light interference microscopy which combines phase contrast microscopy, which renders high contrast intensity images of transparent specimens , and holography, where the phase information from the obj ect is recorded .
  • digital holographic microscopy where the light wave front information corresponding to an obj ect is digitally recorded as a hologram .
  • the obj ect image is calculated by using a numerical reconstruction algorithm .
  • TIE transport-of- intensity equation
  • the TIE relates changes in phase in an x-y plane to changes in phase in a z direction ( along the optical axis ) by the calculation of the deviation between two brightfield images with a defined di f ference in z .
  • a z-stack of images with an automated scan software is required, which needs precise z-movement and acquisition time .
  • Another optical technique to enhance contrast of transparent specimens is differential interference contrast (DIG) .
  • DIG differential interference contrast
  • DIG comprises a light source, a polarizer, a first Wollaston prism, a condenser, an objective lens, a second Wollaston prism and an analyzer.
  • Unpolarized light emitted from the light source is polarized by the polarizer.
  • the first Wollaston prism separates the polarized light into perpendicularly polarized components with a spatial offset defined by the Wollaston prism.
  • the condenser lens directs the polarized components onto the probe.
  • the objective lens directs the light after going through the probe onto the second Wollaston prism which compensates the nominal spatial offset and recombines the perpendicularly polarized light.
  • the analyzer is a polarizing filter which removes directly transmitted light.
  • DIG can be used for example for classification of unstained white blood cells (WBC) .
  • the invention provides a device for observing a biological probe .
  • the device comprises an optical microscope , a beam splitting device and a plurality of cameras .
  • the optical microscope comprises a support structure for supporting the biological probe in a beam path of the optical microscope .
  • the beam splitting device is arranged in the beam path downstream from the biological probe , wherein the beam splitting device is configured to split the beam path into a plurality of beam paths .
  • Each camera is arranged in one beam path of the plurality of beam paths and is configured to generate camera images of the biological probe .
  • the invention provides a method for observing a biological probe , using a device according to the first aspect.
  • the method comprises generating at least one camera image of the biological probe by at least one camera of the plurality of cameras of the device.
  • the invention provides a method and a device based on a multi camera set-up with at least two cameras which can e.g. be mounted on a standard inverse microscope port. Therefore, multiple camera images can be generated at the same time, which allows an extensive specimen analysis in less time and with less necessary images.
  • sensor types of the cameras might differ from one another.
  • different sensor types can refer to at least one of a difference in pixel size, a difference in pixel number, a difference in spectral sensitivity or a difference in sensitivity to polarization.
  • some cameras may be monochrome cameras, others RGB cameras.
  • the device comprises at least three cameras.
  • the optical microscope is a polarized light microscope. Accordingly, polarization techniques can be used.
  • the polarized light microscope is an interference-based microscope, in particular an interference reflection microscope.
  • the microscope is a differential interference contrast (DIG) microscope.
  • DIG differential interference contrast
  • Brightfield and DIG imaging can be carried out at the same time. This provides a simple mass producible solution for brightfield and DIG imaging and the possibility of phase calculation in one shot.
  • a non-interf erometric quantitative phase measurement technique is combined with a time saving illumination and contrast process which enables DIG and brightfield image acquisition at one single timepoint.
  • At least one of the cameras is a monochrome camera. That is, the camera is sensitive to a certain wavelength range for all its sensing elements, referred to as pixels.
  • At least one of the cameras is a color camera, e.g. a color prism camera. That is, the camera is sensitive to a broad wavelength region, e.g. in the entire visible light wavelength region.
  • the device combines color image ac- quisition, DIG image acquisition and brightfield image acquisition .
  • the plurality of cameras comprises at least one polarization sensitive camera configured to generate a plurality of camera images corresponding to different polarizations.
  • polarization sensitive camera configured to generate a plurality of camera images corresponding to different polarizations.
  • the sensor can be structured in blocks of pixels, each block can consist of four pixels and has therefore four different orientations on a polarization grid, e.g. 90°, 45°, 0° and 135°.
  • the microscope may be configured as a DIG microscope with the analyzer which is normally placed before the camera being removed.
  • the DIG microscope may comprise a first polarizer and a microscope condenser.
  • the camera pixels with the polarization grid arranged parallel to the polarization axes after the first Wollaston prism show brightfield images and the pixel with the grid orientated under 45° shift to the aforementioned show DIG images. Therefore, both brightfield images and DIG images can be generated at the same time with the polarization sensitive camera.
  • a polarization filter may be mounted directly in front of the camera, arranged in a way that it is perpendicular to the first polarizer in the microscope .
  • the use of special illumination configuration and polarization cameras can reduce the necessary imaging time by a factor of 2 and thus enables the imaging of moving objects.
  • the at least one polarization sensitive camera generates a plurality of camera images corresponding to different pre-defined polarization states.
  • a computing device can use the obtained images at different, defined polarization states for a phase reconstruction.
  • the computing device may compute absorption information from the brightfield image and can be configured to mathematically remove the absorption information from the DIG images. Therefore, quantitative height information of the specimen can be obtained.
  • the phase and optionally additionally RBC parameters may be calculated from two DIG images, which differ only in the directional information (i.e. which of the two beams separated in the 1st Wollaston prism is delayed) , e.g. using the method described in Shibata et al., “Video-rate quantitative phase analysis by a DIG microscope using a polarization camera,” Biomed. Opt. Express 10, 1273-1281 (2019) .
  • the parallel acquisition of both contrast methods i.e. acquiring brightfield and DIG information
  • An example of a combined use of brightfield and DIG information is the analysis of unstained WBC .
  • the classification of WBC in, e.g., the five major groups can be done via Artificial Intelligence analysis.
  • RBC parameters can be measured. This enables an application of the measurement set-up for an optical complete blood count .
  • the device further comprises a computing device configured to generate a DIG image based on a mathematical combination of the camera images corresponding to the different polarizations.
  • the combination can be determined in a calibration phase.
  • the computing device is configured to generate a brightfield image based on a mathematical combination of the camera images corresponding to the different polarizations.
  • the combination can be determined in a calibration phase.
  • the device further comprises a computing device configured to carry out a transport-of-intensity- equation, TIE, -based phase reconstruction based on the camera images of the cameras.
  • TIE transport-of-intensity- equation
  • the TIE has the following form, as described, e.g. in Frank et al., "Non-interf erometric, noniterative phase retrieval by Green's functions", 2010:
  • X is the wavelength
  • I (x,y,z) is the irradiance at point (x,y,z)
  • ⁇ I> is the phase of the wave.
  • the TIE expresses the dependence between the intensity and the phase distribution and allows to reconstruct the phase of a wave.
  • the system offers the advantages of a TIE microscopy setup without complex movable components, solving the problem of stability and reproducibility in production.
  • the TIE-based phase reconstruction can then be used for example in combination with brightfield- images to derive absorption information for the determination of hemoglobin concentration and volume of RBCs on a single cell level.
  • phase measurement using the TIE based on multiple cameras gives several advantages.
  • the cost is reduced, no movement in the z-direction is necessary, the approach is cheaper than e.g. tunable lenses, there is a reduction of phase noise by acquisition of z and z+dz images at one time point, and a flexible wavelength choice is possible because there is no correction needed as in interferometric set-ups, and the device can therefore be adapted easily to different specimens or buffer systems.
  • the cameras are synchronized to generate camera images of the biological probe at the same time. This reduces or even removes the influence of moving components of the biological probe.
  • synchronization can refer to starting the exposure at the same time.
  • the start point of the exposure might be identical and the gain is optimized (ideally equal to 1 to not amplify noise) but the exposure times differ. In some cases, gain might be adjusted (increased) to get a given frame rate to secure throughput of the imaging system. A blurring effect between images of different exposure time could serve as estimate for the movement of objects.
  • all exposure times may be the same, but the gains might differ to not saturate some of the camera signals .
  • the cameras are firmly attached at predefined locations. That is, the cameras are arranged at predefined or preset distances. This provides much more stability and reproducibility for capturing the images, e.g. for a TIE evaluation.
  • the computation can speed up, therefore reducing the time for reconstruction.
  • the device does not comprise moving parts with changeable distances. This significantly improves the accuracy of the measurement.
  • the amount of available light for capturing images with a respective camera is not or only marginally affected as compared to sequential acquisition of images, so that a high parallelization of the process and thus a high throughput can be achieved for the measurements .
  • a computing device carries out a registration of at least some of the images of the di f ferent cameras .
  • i f corresponding z and z+dz images are used to calculate the derivative of the intensity, the images must be aligned to each other in a proper way .
  • the final pixel-by-pixel registration may be done by computational analysis .
  • the beam splitting device is arranged after one common tubelens in the optical beampath .
  • the beam splitting device is arranged after one common tubelens in the optical beampath .
  • an optical bandpass filter is arranged in front of at least some of the cameras .
  • the bandpass filters can di f fer for at least some of the cameras such that wavelength ranges captured by the cameras for generating camera images of the biological probe di f fer from one another .
  • the device comprises a light source for emitting a light beam .
  • the light source can be a customi zed multi-LED light source , with narrow bandwidth, e . g . achieved by respective bandpass filters .
  • At least two cameras of the plurality of cameras of the device simultaneously generate a respective camera image of the biological probe .
  • the method further comprises the step of generating a DIG image based on a mathematical combination of the camera images corresponding to di f ferent polari zations .
  • the method further comprises the step of carrying out a TIE-based phase reconstruction based on the camera images of the cameras .
  • Fig . 1 schematically shows a block diagram illustrating a device for observing a biological probe according to an embodiment of the invention
  • Fig . 2 schematically shows a block diagram illustrating a device for observing a biological probe according to a further embodiment of the invention
  • Fig . 3 shows a flow diagram for a method for observing a biological probe according to an embodiment of the invention .
  • Figure 1 schematically illustrates a device la for observing a biological probe .
  • the device la comprises an optical microscope 2a, a beam splitting device 3a and a plurality of cameras 41a to 4na .
  • n denotes an integer greater than or equal to 2 which indicates the number of di f ferent cameras .
  • the invention is not restricted to any speci fic number of cameras .
  • At least one of the cameras 41a to 4na can be a color camera . Further, at least one of the cameras 41a to 4na can be a polari zation sensitive camera . At least one of the cameras 41a to 4na can also be a monochromatic camera .
  • the optical microscope 2a comprises a support structure for supporting the biological probe in a beam path of the optical microscope .
  • the beam splitting device 3a is arranged in the beam path downstream from the biological probe and splits the beam into a plurality of beams directed towards a respective camera 41a to 4na .
  • Each camera 41a to 4na acquires an image and provides the image to a computing device 5 .
  • the optical microscope 2a can be a polari zed light microscope , for instance a di f ferential interference contrast microscope .
  • at least one of the cameras 41a to 4na can be a polari zation sensitive camera, having di f ferent types of pixels which are sensitive to di f ferent polari zations .
  • respective camera images are acquired .
  • a first mathematical combination can be found which corresponds to a DIG image .
  • another mathematical combination may be found which corresponds to a brightfield image.
  • Some of the cameras 41a to 4na may acquire camera images of different colors. That is, the cameras 41a to 4na are sensitive to different wavelength regions, i.e. by using bandpass filters.
  • the wavelength ranges captured by the cameras for generating the camera images of the biological probe may only partially differ from one another, i.e., there may be a certain overlap of the wavelength ranges.
  • the focal lengths of the cameras differ from each other.
  • all of the cameras 41a to 4na are mounted at fixed positions and are not movable .
  • the computing device 5 can be configured to carry out a TIE-based phase reconstruction or a DIC-based phase reconstruction.
  • the cameras 41a to 4na are synchronized to generate camera images of the biological probe at the same time.
  • the cameras 41a to 4na may differ with respect to a sensor type, such as pixel sizes or pixel numbers.
  • the computing device 5 may comprise hardware and software components.
  • the hardware components may comprise at least one of microcontrollers, central processing units (CPU) , graphical processing units (GPU) , memories and storage devices.
  • FIG. 2 schematically illustrates a further device lb for analyzing a biological probe.
  • the device lb comprises a microscope 2b which is a differential interference contrast microscope.
  • the microscope 2b comprises a light source which comprises a first LED 201, a second LED 202 and a third LED 203.
  • Each of the first and second LEDs 201 to 203 emits a single light beam with a specific wavelength and bandwidth, wherein the wavelengths of the LEDs 201 to 203 differ from each other.
  • the light source further comprises a first dichroic mirror or beam combiner 204 and a second dichroic mirror or beam combiner 205 which combine the light beams emitted by the first to third LEDs 201 to 203 into a single light beam.
  • the wavelength dependent transmission and/or reflection properties of the respective beam combiners 204 and 205 may also be used to taylor the spectral and/or polarisation properties of the combined single beam according to the requirements of the measurements planned. This beam conditioning helps to reduce the light budget interacting with the biological sample to reduce potential harm to the sample, e.g. drying, bleaching and/or heating, while imaging it.
  • This resulting light beam typically is unpolarized and is directed through a first aperture 206 towards a polarizer 207 for polarizing the light beam.
  • the polarizer 207 can be a linear polarizer with a polarization plane tilted by 45° with respect to the x-axis of the respective imaging sensor coordinate system and is named 45° polarizing filter.
  • a first Wollaston prism 208 separates the polarized light beam into perpendicularly polarized components and spatially separates the two polarized components by a given lateral offset. After passing a second aperture 209, the polarized components are directed towards a support structure 210 holding the biological probe.
  • a second Wollaston prism 211 re-combines the perpendicularly polarized light and compensates for the spatial offset after passing through the biological probe.
  • An analyzer 212 removes directly transmitted light.
  • the analyzer 212 can be a 135° polarizing filter.
  • In the beam path of the optical microscope arranged between the second Wollaston prism 211 and the analyzer 212 , there is a first beam splitter 31 which splits the light beam of the light passing through the second Wollaston prism 211 into a first light beam, directed toward the analyzer 212 , and a second light beam, directed towards a second beam splitter 32 .
  • the first light beam After passing the analyzer 212 , the first light beam is directed towards a first camera 41b .
  • the first camera 41b captures respective camera images .
  • the second light beam is split by the second beam splitter 32 into a third light beam and a fourth light beam .
  • the third light beam goes through a first filter 61 which is a bandpass filter with a first frequency range , for example comprising a frequency of light emitted by the third LED 203 , and enters a second camera 42b .
  • the fourth light beam is directed towards a third beam splitter 33 and split into a fi fth light beam and a sixth light beam .
  • the fi fth light beam goes through a second filter 62 which is a bandpass filter with a second frequency range , for example comprising a frequency of light emitted by the second LED 202 , and enters a third camera 43b .
  • the sixth light beam goes through a third filter 63 which is a bandpass filter with a third frequency range , for example comprising a frequency of light emitted by the first LED 201 , and enters a fourth camera 43b .
  • a third filter 63 which is a bandpass filter with a third frequency range , for example comprising a frequency of light emitted by the first LED 201 , and enters a fourth camera 43b .
  • the first to third beam splitters 31 to 33 form a beam splitting device for generating respective light beams directed towards the first to fourth cameras 41a to 44d .
  • the first camera 41b may be a standard microscope camera .
  • wavelength ranges captured by the cameras 42b to 44b for generating camera im- ages of the biological probe are defined by the respective first to third filters 61 to 63 and differ from one another. That is, each camera 42b to 44b is generating images of the biological probe in a different wavelength region, i.e. at different colors.
  • the second camera 42b, third camera 43b and fourth camera 44b have a first focal length, second focal length and third focal length, respectively.
  • the first to third focal lengths all differ from one another.
  • the second camera 42b, third camera 43b and fourth camera 44b can be positioned in different optical distances on a slider, such that the acquired images have a defined focal distance difference.
  • all cameras are firmly mounted.
  • both the wavelength ranges captured by the second to fourth cameras 42b to 44b and the focal lengths of the second to fourth cameras 42 to 44b all differ from one another.
  • only the wavelength ranges may differ from one another or only the focal lengths may differ from one another.
  • a computing device 5 receives the camera images from the first to fourth cameras 41b to 44b. Based on the camera images from the second to fourth cameras 42b to 44b, the computing device 5 may carry out a TIE-based phase reconstruction.
  • the image from the first camera 41b is a DIG image. All images may be generated at the same time. That is, the first to fourth cameras 41b to 44b may be synchronized to generate images at the same time.
  • the analyzer 212 is absent and the first camera 41b is a polarization dependent camera.
  • the computing device 5 may generate a DIG image based on a first mathematical combination of camera images corresponding to different polarizations, acquired by the polarization de- pendent camera .
  • the computing device 5 may further generate a brightfield image based on a second mathematical combination of camera images corresponding to di f ferent polari zations .
  • Figure 3 shows a flow diagram for a method for analyzing a biological probe .
  • the method may be carried out with one of the devices la, lb shown in figures 1 and 2 and described above . That is , the camera used in the method comprises an optical microscope 2a, 2b with a support structure 210 for supporting the biological probe .
  • a beam splitting device 3a, 3b splits a beam path of the optical microscope 2a, 2b into a plurality of beam paths directed towards a plurality of cameras 41a-4na, 41b-44b .
  • a first method step S I at least one of the cameras 41a- 4na, 41b-44b generates a camera image of the biological probe .
  • some or all cameras 41a-4na, 41b-44b are synchroni zed and generate camera images at the same time .
  • a computing device 5 may carry out a TIE-based reconstruction based on camera images of cameras 41a-4na, 41b-44b with di f ferent focal lengths . Additionally or alternatively, the computing device 5 may generate a DIG image and/or a brightfield image .

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  • Physics & Mathematics (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Engineering & Computer Science (AREA)
  • Multimedia (AREA)
  • Computer Vision & Pattern Recognition (AREA)
  • Microscoopes, Condenser (AREA)
  • Investigating Or Analysing Materials By Optical Means (AREA)

Abstract

L'invention concerne un dispositif d'observation d'une sonde biologique. Le dispositif comprend un microscope optique, un dispositif de division de faisceau et une pluralité de caméras. Le microscope optique comprend une structure de support pour supporter la sonde biologique dans un trajet de faisceau du microscope optique. Le dispositif de division de faisceau est agencé dans le trajet de faisceau en aval de la sonde biologique, le dispositif de division de faisceau étant conçu pour diviser le trajet de faisceau en une pluralité de trajets de faisceau. Chaque caméra est agencée dans un trajet de faisceau de la pluralité de trajets de faisceau et est configurée pour générer des images de caméra de la sonde biologique. Pour au moins certaines des caméras, les distances focales des caméras diffèrent les unes des autres et/ou des plages de longueurs d'onde capturées par les caméras pour générer les images de caméra de la sonde biologique diffèrent les unes des autres et/ou des types de capteurs des caméras (41a-4na ; 41b-44b) diffèrent les uns des autres.
PCT/EP2022/072401 2021-08-19 2022-08-10 Dispositif et procédé d'observation d'une sonde biologique WO2023020902A1 (fr)

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EP21192048.3A EP4137863A1 (fr) 2021-08-19 2021-08-19 Dispositif et procédé d'observation de sonde biologique

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Citations (5)

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WO2015121853A1 (fr) * 2014-02-13 2015-08-20 B. G. Negev Technologies And Applications Ltd., At Ben-Gurion University Microscopie à cohérence optique plein champ en mode double et en temps réel avec imagerie pleine gamme
US20180089817A1 (en) * 2016-09-26 2018-03-29 Carl Zeiss Smt Gmbh Method for determining a distance between a first structure element on a substrate and a second structure element
EP3575848A1 (fr) * 2018-05-30 2019-12-04 Siemens Healthcare Diagnostics Inc. Analyseur destiné à l'analyse tridimensionnelle d'un échantillon médical au moyen d'un appareil photographique plénoptique
WO2021155363A1 (fr) * 2020-01-31 2021-08-05 Photothermal Spectroscopy Corp. Procédé et appareil pour spectroscopie et imagerie infrarouge photothermique à large champ haute performance

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PHILLIPS: "Quantitative optical microscopy measurement of cellular biophysical features with a standard optical microscope", J. VIS. EXP., vol. 86, 2014, pages 50988
QUAN XIANGYU ET AL: "Multimodal Microscopy: Fast Acquisition of Quantitative Phase and Fluorescence Imaging in 3D Space", IEEE JOURNAL OF SELECTED TOPICS IN QUANTUM ELECTRONICS, IEEE, USA, vol. 27, no. 4, 16 November 2020 (2020-11-16), pages 1 - 11, XP011825326, ISSN: 1077-260X, [retrieved on 20201211], DOI: 10.1109/JSTQE.2020.3038403 *
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